Pancreatic cancer is one of the most common forms of malignant disease with a poor survival prognosis. Currently, nanomedicine holds great promise for targeted diagnosis and treatment of this cancer, which also reduces toxic side effects. In this work, we prepared PEG-coated monodisperse upconversion nanoparticles (UCNPs) with a conjugated Flamma® fluorescent dye for imaging and detection of particle distribution in vivo. We performed a thorough physicochemical characterization of the particles and determined their colloidal and chemical stability in several aqueous media such as water, PBS, Dulbecco's modified Eagle's medium and artificial lysosomal fluid. Luminescence resonance energy transfer from the emission of UCNPs as a donor to the Flamma® as an acceptor was confirmed. Intraperitoneal versus intravenous administration was then compared in terms of biodistribution of particles in various organs in the orthotopic mice pancreatic cancer model. The intraperitoneal route was preferred over the intravenous one, because it significantly increased the accumulation of particles in the tumor tissue. These new UCNP@Ale-PEG-Flamma® nanoparticles are thus promising for new treatment avenues for pancreatic cancer.

• Publikační typ
• časopisecké články MeSH

Photodynamic therapy (PDT) has the potential to cure pancreatic cancer with minimal side effects. Visible wavelengths are primarily used to activate hydrophobic photosensitizers, but in clinical practice, these wavelengths do not sufficiently penetrate deeper localized tumor cells. In this work, NaYF4:Yb3+,Er3+,Fe2+ upconversion nanoparticles (UCNPs) were coated with polymer and labeled with meta-tetra(hydroxyphenyl)chlorin (mTHPC; temoporfin) to enable near-infrared light (NIR)-triggered PDT of pancreatic cancer. The coating consisted of alendronate-terminated poly[N,N-dimethylacrylamide-co-2-aminoethylacrylamide]-graft-poly(ethylene glycol) [P(DMA-AEM)-PEG-Ale] to ensure the chemical and colloidal stability of the particles in aqueous physiological fluids, thereby also improving the therapeutic efficacy. The designed particles were well tolerated by the human pancreatic adenocarcinoma cell lines CAPAN-2, PANC-1, and PA-TU-8902. After intratumoral injection of mTHPC-conjugated polymer-coated UCNPs and subsequent exposure to 980 nm NIR light, excellent PDT efficacy was achieved in tumor-bearing mice.

• MeSH
• akrylamidy chemie   MeSH
• fotochemoterapie * metody   MeSH
• fotosenzibilizující látky * chemie   farmakologie   MeSH
• infračervené záření MeSH
• koloidy chemie   MeSH
• lidé MeSH
• mesoporfyriny * chemie   farmakologie   MeSH
• myši inbrední BALB C MeSH
• myši nahé MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nádory slinivky břišní * farmakoterapie   patologie   MeSH
• nanočástice chemie   MeSH
• polyethylenglykoly * chemie   MeSH
• polymery chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• akrylamidy MeSH
• fotosenzibilizující látky * MeSH
• koloidy MeSH
• mesoporfyriny * MeSH
• polyethylenglykoly * MeSH
• polymery MeSH
• temoporfin MeSH Prohlížeč

In this study, spherical or hexagonal NaYF4:Yb,Er nanoparticles (UCNPs) with sizes of 25 nm (S-UCNPs) and 120 nm (L-UCNPs) were synthesized by high-temperature coprecipitation and subsequently modified with three kinds of polymers. These included poly(ethylene glycol) (PEG) and poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide) [P(DMA-AEA)] terminated with an alendronate anchoring group, and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The internalization of nanoparticles by rat mesenchymal stem cells (rMSCs) and C6 cancer cells (rat glial tumor cell line) was visualized by electron microscopy and the cytotoxicity of the UCNPs and their leaches was measured by the real-time proliferation assay. The comet assay was used to determine the oxidative damage of the UCNPs. An in vivo study on mice determined the elimination route and potential accumulation of UCNPs in the body. The results showed that the L- and S-UCNPs were internalized into cells in the lumen of endosomes. The proliferation assay revealed that the L-UCNPs were less toxic than S-UCNPs. The viability of rMSCs incubated with particles decreased in the order S-UCNP@Ale-(PDMA-AEA) > S-UCNP@Ale-PEG > S-UCNPs > S-UCNP@PMVEMA. Similar results were obtained in C6 cells. The oxidative damage measured by the comet assay showed that neat L-UCNPs caused more oxidative damage to rMSCs than all coated UCNPs while no difference was observed in C6 cells. An in vivo study indicated that L-UCNPs were eliminated from the body via the hepatobiliary route; L-UCNP@Ale-PEG particles were almost eliminated from the liver 96 h after intravenous application. Pilot fluorescence imaging confirmed the limited in vivo detection capabilities of the nanoparticles.

• Klíčová slova
• biological applications, toxicity, upconverting nanoparticles,
• MeSH
• krysa rodu Rattus MeSH
• mezenchymální kmenové buňky * metabolismus   účinky léků   cytologie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• nanočástice chemie   MeSH
• oxidační stres účinky léků   MeSH
• polyethylenglykoly chemie   MeSH
• velikost částic MeSH
• viabilita buněk účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• polyethylenglykoly MeSH

In this report, upconverting NaYF4:Yb3+,Er3+ nanoparticles (UCNPs) were synthesized by high-temperature coprecipitation of lanthanide chlorides and encapsulated in poly(glycerol monomethacrylate) (PGMMA). The UCNP surface was first treated with hydrophobic penta(propylene glycol) methacrylate phosphate (SIPO) to improve colloidal stability and enable encapsulation by reversible addition-fragmentation chain transfer miniemulsion polymerization (RAFT) of glycidyl methacrylate (GMA) in water, followed by its hydrolysis. The resulting UCNP-containing PGMMA particles (UCNP@PGMMA), hundreds of nanometers in diameter, were thoroughly characterized by transmission (TEM) and scanning electron microscopy (SEM), dynamic light scattering (DLS), infrared (FTIR) and fluorescence emission spectroscopy, and thermogravimetric analysis (TGA) in terms of particle morphology, size, polydispersity, luminescence, and composition. The morphology, typically raspberry-like, depended on the GMA/UCNP weight ratio. Coating of the UCNPs with hydrophilic PGMMA provided the UCNPs with antifouling properties while enhancing chemical stability and reducing the cytotoxicity of neat UCNPs to a non-toxic level. In addition, it will allow the binding of molecules such as photosensitizers, thus expanding the possibilities for use in various biomedical applications.

• Publikační typ
• časopisecké články MeSH

Large (120 nm) hexagonal NaYF4:Yb, Er nanoparticles (UCNPs) were synthesized by high-temperature coprecipitation method and coated with poly(ethylene glycol)-alendronate (PEG-Ale), poly (N,N-dimethylacrylamide-co-2-aminoethylacrylamide)-alendronate (PDMA-Ale) or poly(methyl vinyl ether-co-maleic acid) (PMVEMA). The colloidal stability of polymer-coated UCNPs in water, PBS and DMEM medium was investigated by dynamic light scattering; UCNP@PMVEMA particles showed the best stability in PBS. Dissolution of the particles in water, PBS, DMEM and artificial lysosomal fluid (ALF) determined by potentiometric measurements showed that all particles were relatively chemically stable in DMEM. The UCNP@Ale-PEG and UCNP@Ale-PDMA particles were the least soluble in water and ALF, while the UCNP@PMVEMA particles were the most chemically stable in PBS. Green fluorescence of FITC-Ale-modified UCNPs was observed inside the cells, demonstrating successful internalization of particles into cells. The highest uptake was observed for neat UCNPs, followed by UCNP@Ale-PDMA and UCNP@PMVEMA. Viability of C6 cells and rat mesenchymal stem cells (rMSCs) growing in the presence of UCNPs was monitored by Alamar Blue assay. Culturing with UCNPs for 24 h did not affect cell viability. Prolonged incubation with particles for 72 h reduced cell viability to 40%-85% depending on the type of coating and nanoparticle concentration. The greatest decrease in cell viability was observed in cells cultured with neat UCNPs and UCNP@PMVEMA particles. Thanks to high upconversion luminescence, high cellular uptake and low toxicity, PDMA-coated hexagonal UCNPs may find future applications in cancer therapy.

• Klíčová slova
• cell viability, dissolution, lanthanides, luminescence, nanoparticles, upconversion, uptake,
• Publikační typ
• časopisecké články MeSH

Upconverting nanoparticles (UCNPs) are of particular interest in nanomedicine for in vivo deep-tissue optical cancer bioimaging due to their efficient cellular uptake dependent on polymer coating. In this study, particles, ca. 25 nm in diameter, were prepared by a high-temperature coprecipitation of lanthanide chlorides. To ensure optimal dispersion of UCNPs in aqueous milieu, they were coated with three different polymers containing reactive groups, i.e., poly(ethylene glycol)-alendronate (PEG-Ale), poly(N,N-dimethylacrylamide-co-2-aminoethylacrylamide)-alendronate (PDMA-Ale), and poly(methyl vinyl ether-co-maleic acid) (PMVEMA). All the particles were characterized by TEM, DLS, FTIR, and spectrofluorometer to determine the morphology, hydrodynamic size and ξ-potential, composition, and upconversion luminescence. The degradability/dissolution of UCNPs in water, PBS, DMEM, or artificial lysosomal fluid (ALF) was evaluated using an ion-selective electrochemical method and UV-Vis spectroscopy. The dissolution that was more pronounced in PBS at elevated temperatures was decelerated by polymer coatings. The dissolution in DMEM was relatively small, but much more pronounced in ALF. PMVEMA with multiple anchoring groups provided better protection against particle dissolution in PBS than PEG-Ale and PDMA-Ale polymers containing only one reactive group. However, the cytotoxicity of the particles depended not only on their ability to rapidly degrade, but also on the type of coating. According to MTT, neat UCNPs and UCNP@PMVEMA were toxic for both rat cells (C6) and rat mesenchymal stem cells (rMSCs), which was in contrast to the UCNP@Ale-PDMA particles that were biocompatible. On the other hand, both the cytotoxicity and uptake of the UCNP@Ale-PEG particles by C6 and rMSCs were low, according to MTT assay and ICP-MS, respectively. This was confirmed by a confocal microscopy, where the neat UCNPs were preferentially internalized by both cell types, followed by the UCNP@PMVEMA, UCNP@Ale-PDMA, and UCNP@Ale-PEG particles. This study provides guidance for the selection of a suitable nanoparticle coating with respect to future biomedical applications where specific behaviors (extracellular deposition vs. cell internalization) are expected.

• Klíčová slova
• degradation, lanthanides, luminescence, nanoparticles, upconversion,
• MeSH
• alendronát MeSH
• krysa rodu Rattus MeSH
• nanočástice * chemie   MeSH
• polyethylenglykoly chemie   MeSH
• polymery * chemie   MeSH
• voda MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• alendronát MeSH
• polyethylenglykoly MeSH
• polymery * MeSH
• voda MeSH